Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2 CHSPSC, LLC Antimicrobial Stewardship Education Series ProCE, Inc. www.ProCE.com 1 CHSPSC, LLC Antimicrobial Stewardship Education Series June 14, 2017 Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2 Featured Speaker: Larry Danziger, Pharm.D. Professor of Pharmacy and Medicine University of Illinois at Chicago 2 Submission of an online post‐test and evaluation is the only way to obtain CE credit for this webinar Go to www.ProCE.com/CHSRx Webinar attendees will also receive an email with a direct link to the web page Print your CE statement of completion online – Credit for live or enduring (not both) Deadline: July 14, 2017 CPE Monitor (applicable to pharmacists) – CE credit automatically uploaded to NABP/CPE Monitor upon completion of post‐test and evaluation (user must complete the “claim credit” step) Online Evaluation, Self-Assessment and CE Credit Attendance Code Code will be provided at the end of today’s activity
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
ProCE, Inc.www.ProCE.com 1
CHSPSC, LLC Antimicrobial Stewardship Education Series
June 14, 2017Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2
Featured Speaker:
Larry Danziger, Pharm.D.Professor of Pharmacy and MedicineUniversity of Illinois at Chicago
2
Submission of an online post‐test and evaluation is the only way to obtain CE credit for this webinar
Go to www.ProCE.com/CHSRx Webinar attendees will also receive an email with a direct link to the
web page Print your CE statement of completion online
– Credit for live or enduring (not both)
Deadline: July 14, 2017 CPE Monitor (applicable to pharmacists)
– CE credit automatically uploaded to NABP/CPE Monitor upon completion of post‐test and evaluation (user must complete the “claim credit” step)
Online Evaluation, Self-Assessmentand CE Credit
Attendance Code
Code will be provided at the end of today’s activity
Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
ProCE, Inc.www.ProCE.com 2
How to Ask a Question
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
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2016 Pharmacy Education Series
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It is the policy of ProCE, Inc. to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Dr. Danziger has disclosed the following financial/commercial relationships: Speaker for Allergan, MedCo, and Merck.
Please note: The opinions expressed in this activity should not be construed as those of the CME/CE provider. The information and views are those of the faculty through clinical practice and knowledge of the professional literature. Portions of this activity may include unlabeled indications. Use of drugs and devices outside of labeling should be considered experimental and participants are advised to consult prescribing information and professional literature.
June 14, 2017Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2
Featured Speaker:
Larry Danziger, Pharm.D.Professor of Pharmacy and MedicineUniversity of Illinois at Chicago
CE Activity Information & Accreditation
ProCE, Inc. (Pharmacist CE)
– 1.0 contact hour
6
Funding:This activity is self‐funded through CHSPSC.
Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
AUC/MIC >100 Daptomycin or >50 Colistin or > 400 Vancomycin
Time (Hours) 24 Hours 13
Dosing Mystery
How is the proper dose and dosage interval determine?
In some instances, agents whose half-lives in serum differ by as much as 10 to 18-fold have been administered at the same dosage, with the same interval between doses
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
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Garnacho-Montero et al
Luna et al
0 20 40 60 80 100
Ibrahim et al
Alvarez-Lerma
Rello et al
Mortality (%)
Vallés et al
Rello et al. Am J Respir Crit Care Med 1997;156:196–200; Alvarez-Lerma. Intensive Care Med 1996;22:387–394Ibrahim et al. Chest 2000;118:146–155; Vallés et al. Chest 2003;123:1615–1624Luna et al. Chest 1997;111:676–685 Garnacho-Montero et al. Crit Care Med 2003;31:2742–2751;
Mortality Associated with Appropriate Therapy (Critically Ill Patients)
Why continued Mortality? Delay of initial therapy
Inadequate drug exposure
Wrong dose
Persistence of disease process
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Do We Deliver Effective Doses in Critically Ill Patients
Prospective, observational study to assess clinical and microbiologic response rates in 19 critically ill patients with empiric therapy
Only 3/19 patients met appropriate PK/PD target goal with initial empiric antibiotic
After dose changed to appropriate PK/PD target goal
– 17/19 (89%) patients had a clinical cure or improvement
– 16/19 (84%) had either microbiologic eradication or presumed eradication
Mohr JF, et al. Diagn Micro Infect Dis 2004;48:125-30.16
Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
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Pharmacokinetic /Pharmacodynamic Considerations
• Beta-Lactams– PK/PD Effect relationships
– Dosage regimen design
• Gentamicin– PK/PD Effect relationships
– Dosage regimen design
• Vancomycin– PK/PD Effect relationships
– Dosage regimen design
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Optimization of β-lactams
• β-Lactam antibiotics are the most widely produced and used antibacterial drugs in the world, and have been ever since their initial clinical trials in 1941
• The critical parameter is the time the antibiotic concentration remains above the MIC of the organism expressed as
– T > MIC
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
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Optimization of β-lactams
• Duration of exposure was documented as being important for β-lactam antibiotics more than 70 years ago (Eagle 1940s and Schmidt 1950s)
• Noted most effective way to treat an infection with penicillin (a β-lactam) was to maintain MIC in the plasma throughout the course of treatment
• Repository formulations of penicillin G, were designed to maintain concentrations of the drug above the MIC in plasma and tissues for protracted time periods
Chain E, et al. Lancet 1940, 1: 226-228Schmidt L, Walley A, J Pharmacol Ther 1951, 103: 479-488 19
Serum Concentrations of Penicillin GVarious Routes of Administration
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
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Intravenous Therapy(A History)
• First IV antibiotic penicillin administered at Mass General in 1940s
• Until about the 1930s-1940s, the administration of IV fluids and medications was usually performed by physicians
• In fact, in some locations, IV cannulation and IV medication administration remained exclusively a medical role until about the 1970s
Millam D. J Intraven Nur, 1996;19:5-14 Reusable Syringe Kit (1880s)21
• Continuous intravenous infusions of penicillin fell out of favor as a treatment strategy in the 1960s
• IV medications were often only given during the day
• In the 1950s and 1960s fear of IV administration because
• Bottle might fall on the patient
• Air embolus of solution running out
• Toxicity associated with accidental over administration of fluid and drug
Millam D. J Intraven Nur, 1996;19:5-14
Intravenous Therapy(A History)
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• Research of continuous infusion β-lactams in humans again occurs in earnest again in the late 1970s– Febrile neutropenic patients
– Carbenicillin + intermittent or continuous infusion cefamandole
– ↑ cure rates with continuous vs. intermittent infusion
Bodey GP, et al. Am J Med 1979;67:608-616.
Optimization of β-lactams
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The optimum level of exposure varies for different agents within the beta-lactam class
Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
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Optimization of β-lactams
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Concentration
Time
MIC
Intermittent Infusion
Ceftazidime 2g Q8h = TDD 6g
Ceftazidime 3g daily Continuous Infusion
Optimization of β-lactams(Ceftazidime)
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
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• Greater T > MIC (bactericidal)
• Less antimicrobial over treatment duration
– e.g., ceftazidime 2g Q8h vs. 3g CI over 24 hours
• Similar clinical and microbiological outcomes
– Reduced time to temperature normalization
• Cost savings observed
Kuti JL, et al. Clin Ther 2004;26:493-501 Grant EM, et al. Pharmacother 2002;22:471-483. Boselli E, et al. Crit Care Med 2003;31:2102-2106. Nicolau DP, et al. Int J Antimicrob Agents 2001;17:497-504. Thalhammer F, et al. J Antimicrob Chemother 1999;43:523-527;35:391-402.
Optimization of β-lactams(Ceftazidime)
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• Cefepime Intermittent infusion 1g q8h over 30 minutes (n=51) vs Extended infusion 2g q8h over 4 hours (n =35)
• Extended infusion resulted in:– Reduced LOS in ICU 18.5 vs. 8 days
– Reduced hospital mortality at 14 days was 20 vs 3%
– Reduced Cost of Care $53,000 vs. $30,000 USD
Bauer KA, et al., Antimicrob Agents Chemo 2013;57(7):2907-2912
Optimization of β-lactams(Cefepime)
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
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1.0 mcg/ml
Cirillo I et al. J Clin Pharm. 2009;7:798
Optimization of β-lactams(Doripenem)
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• A recent randomized trial in VAP patients comparing doripenem 4 hr extended-infusion with imipenem-cilastatin was prematurely terminated because of higher rates of clinical failures and mortality in the doripenem
• In the MITT clinical cures was lower in the doripenem treated patients 45.6% vs 56.8% in imipenem-cilistatin patients
• In the intent-to-treat population, the 28-day all-cause mortality was higher in the doripenem arm (23.0 percent; n=31/135) than in the imipenem-cilastatin arm (16.7 percent; n=22/132)
Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
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Meta-analysis to determine whether prolonged β-lactam infusions were associated with a reduction in mortality and improvement in clinical success
A search of PubMed, EMBASE and The Cochrane Library for randomized controlled trials (RCTs) and observational studies comparing prolonged infusion with intermittent bolus administration of the same antibiotic in hospitalized adult patients was conducted
Primary outcomes evaluated were mortality and clinical success
A total of 29 studies with 2206 patients (18 RCTs and 11 observational studies) were included in the meta-analysis
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Prolonged Infusion vs Intermittent Boluses of β-lactam Antibiotics
(A meta-analysis )
Teo J et al, Inter J of Antimicrob Agents 2014; 43: 403-411
Clinical Success Mortality
Use of prolonged infusion appears to be associated with improvement in clinical success (RR=1.12,95% CI 1.03-1.21)
Use of prolonged infusion appears to be associated with improvement in mortality (RR=1.12,95% CI 1.03-1.21)
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
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Optimization of β-lactams
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• Although studies to date thus far very small
• Clinical data suggest that prolonged infusions are at least as effective as intermittent infusions for gram-negative infections
• More randomized, well powered studies needed
• May not be necessary for all bacteria ( or infections)
• Questionable role: Critically ill patients with meningitis, VAP, or those with suspected or confirmed MDR pathogen
Gillespie EL, et al. Expert Opin Drug Metab Toxicol 2005;1:351-61 Lodise TP, et al. CID 2007;44:357-63 Teo J et al, Inter J of Antimicrob Agents 2014; 43: 403-411
Optimization of β-lactams(Issues for Extended Infusion)
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
• This approach exploits the concentration-dependent killing and post-antibiotic effect of aminoglycosides
• Considered as efficacious as traditional dosing with possibly less toxicity
• However, this strategy has not been adequately studied in all populations
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Meta-Analysis Once Daily Dosing Aminoglycosides
• Randomized, controlled trials that compared intravenous once-daily aminoglycoside regimen with a standard aminoglycoside regimen in infected immunocompetent adults
• Examined efficacy, mortality, or toxicity
• 42 studies were reviewed for possible inclusion
• 13 independent studies met the selection criteria, and their results were pooled
Hatala R et al; Annals of Internal Medicine. 124(8):717‐725, April 15, 1996.36
Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
Hatala, R et al. Annals of Internal Medicine. 124(8):717‐725, April 15, 1996.
Once‐daily compared with standard aminoglycoside dosing. The individual study risk ratios for clinical cure, with 95% CIs. Risk ratios to the left of 1.0 favor standard aminoglycoside dosing; those to the right favor once‐daily aminoglycoside dosing. Test for heterogeneity, P equals 0.07.
Once‐daily compared with standard aminoglycoside dosing. The individual study and pooled risk ratios for nephrotoxicity, with 95% CIs. Risk ratios to the left of 1.0 favor once‐daily aminoglycoside dosing; those to the right favor standard aminoglycoside dosing Test for heterogeneity, P more than 0.2.
Clinical Cure Nephrotoxicity
N equals the total individual study sample for the outcome N equals the total individual study
sample for the outcome
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Once Daily Aminoglycoside Dosing NomogramsInitial Doses and CrCL Based Dosing
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Pharmacokinetics/Pharmacodynamics of Antibiotics: Refresher Part 2CHSPSC, LLC Antimicrobial Stewardship Education Series
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Once-Daily Aminoglycosides
• Most Use Hartford Nomogram
• Recommends a single level be drawn 6 to 14 hours after the dose
• Less intensive monitoring of serum concentrations
• With extended interval dosing there should be no significant accumulation with multiple dosing, therefore, measurements can be obtained after any dose
Freeman C et al. JAC 1997;39:677-686
Nicolau D et al. Antimicrob Agents Chemother 1995; 39:650-65539
Freeman C et al. JAC1997;39:677-686.
Hartford Aminoglycoside Nomogram
Hartford Nomogram 7 mg/Kg OD
If level falls in area designated 24 hours, 36 hours or 48 hours, dosing interval is 24, 36 or 48 hourly respectively.
If level falls on a line between dosing intervals, choose longer interval.
If level is above 48 hour line then STOP the treatment. If gentamicin is to be continued, take daily levels, but do not give any more gentamicin until level falls below 2mg/L 40
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Once-Daily Aminoglycosides• This approach provides high peaks and undetectable
troughs
• Dose: 5-7mg/kg/24hrs (ABW)
• Target peak 14-20 mcg/ml
• Allows low troughs (<1mcg/ml )
• If elevated concentrations noted consider:• Blood collected too early
• Patient not clearing Gentamicin
• Blood collected from lumen used to infuse Gentamicin earlier on
Bertino JS, et al. Clin Infect Dis 1997;24:820-823. Brown GH, et al. Clin Infect Dis 2000;30:440-441. Barclay ML, et al. Clin Pharmacokinet 1999;36:89-98.
Provides therapeutic troughs and peaksConsidered in pts with severe renal failureCheck peak and trough
Appropriate for most patients or good renal function or moderate renal insufficiency. Check a level 8-12 hours after end of infusion
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Vancomycin - Background
– A glycopeptide antibiotic
– Inhibition of cell wall synthesis
– Used IV for treatment of patients with suspected or proven invasive gram-positive infections, including methicillin-resistant Staphylococcus aureus (MRSA)
– Emerging Vancomycin resistance: VRE and VRSA
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Vancomycin Nephrotoxicity and Ototoxicity
• Early reports: impure product
• Nephrotoxicity– May potentiate aminoglycoside nephrotoxicity
– Trough >15 or >20 mg/L
– Css average >28 mg/L
– AUC >952 mg.h/L
• Ototoxicity– Little evidence if monotherapy
– However reported in some patients with vancomycin concentrations > 80 mg/L
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Ebert, S. ICAAC #439, 1987
VancomycinConcentration - Effect Relationships
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• Moise-Broder et al, Clin Pharmacokinet 43: 925, 2004
– 108 patients, MRSA
– Better outcome if ssAUC24 /MIC > 400 mg.h/L
– No relationship with time >MIC
• Jeffres et al, Chest 130: 947, 2006
– 102 patients, retrospective study
– No difference in trough (14 mg/L) or AUC (350 mg.h/L) between survivors and non-survivors (no MIC data)
Obtain trough levels prior to the 4th dose of a new regimen (prior to the 3rd dose for patients with dosing intervals > 24 hours)
Rybak M. Am J Health Sys Pharm 2009;66:82Lui C Clin Infec Dis 2011;52:18 53
Vancomycin Dosing
DOSAGE ADJUSTMENTCreatinine Clearance
> 60 15 mg/kg Every 12 hrs
IV
40-60 15 mg/kg Every 24 hrs
IV
10-40 15 mg/kg Every 48-96 hrs
IV
< 10 15 mg/kg Every 4-7 days
IV
Hemodialysis: No supplementationTarget trough level is 15-20 mcg/mL.
Vancomycin 15 mg/kg Every 12 hrs
IV
Ohio State Dosing Guidelines 2017 - Pneumonia 54
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VancomycinTherapeutic Drug Monitoring
• Monitoring of peak vancomycin concentrations is notrecommended
• Obtain serum troughs at steady state (before 4th or 5th dose)
• For most patients with SSTI with normal renal function and not obese, traditional doses of 1 g Q12 are adequate and trough monitoring is not required
• For serious infections (e.g. bacteremia, endocarditis, osteomyelitis, pneumonia, severe SSTI), target vancomycin trough concentrations of 15-20 g/mL